Characterization of EP receptor subtypes responsible for prostaglandin E-2-induced pain responses by use of EP1 and EP3 receptor knockout mice

1 Prostaglandin E-2 (PGE(2)) is known to be the principal pro-inflammatory prostanoid and play an important role in nociception. To identify PGE recep tor (EP) subtypes that mediate pain responses to noxious and innocuous stim uli, we studied them by use of EP1 and EP3 knockout (EP1- - and EP3- -) mic e. 2 PGE(2) could induce mechanical allodynia in EP1+ +, EP3+ + and EP3- - mic e, but not in EP1- - mice. N-methyl-D-aspartate (NMDA), the substrate of ni tric oxide (NO) synthase L-arginine. or the NO donor sodium nitroprusside a dministered intrathecal (i.t.) could induce allodynia in EP3- - and EP1- - mice. Activation of EPI receptors appears to be upstream, rather than downs tream of NMDA receptor activation and NO production in the PGE(2)-induced a llodynia. 3 Although PGE(2) produced thermal hyperalgesia over a wide range of dosage s from 50 pg to 0.5 mug kg(-1) in EP3+ + mice, it showed a monophasic hyper algesic action at 5 ng kg(-1) or higher doses in EP3- - mice. The selective EP3 agonist, ONO-AE-248, induced hyperalgesia at 500 pg kg(-1) in EP3+ + m ice, but not in EP3-.- mice. 4 Saline-injected EP1- - mice showed hyperalgesia, which was reversed by i. t. PGE(2) in a dose-dependent manner. 5 There was no significant difference in the formalin-induced behaviours be tween EP1- - or EP3- - mice and the cognate wild-type mice. 6 These results demonstrate that spinal EP1 receptors an involved in the PG E(2)-induced allodynia and that spinal EP3 receptors are involved in the hy peralgesia induced by low doses of PGE(2). However, the formalin-induced pa in cannot be ascribed to a single EP1 receptor subtype EP1 or EP3.